ABSTRACT

The broad spectrum antimicrobial/antifungal zinc pyrithione (ZnPT) is used in products ranging from antifouling paint to antidandruff shampoo. The hazard profile of ZnPT was established based upon comprehensive toxicological testing, and products containing this biocide have been safely used for years. The purpose of this study was to create a dermal physiologically based pharmacokinetic (PBPK) model for ZnPT in the rat for improving dose–response analysis of ZnPT-induced toxicity where reversible hindlimb weakness was the endpoint used as the basis for ZnPT risk assessments. Previously, we developed a PBPK model which simulated the kinetics of pyrithione (PT) and its major metabolites 2-(methylsulfonyl)pyridine and S-glucuronide conjugates in blood and tissues of rats following oral ZnPT administration. The dermal model was optimized utilizing in vitro dermal penetration investigations conducted with rat skin and with historical data from a dermal repeat dose study using rats. The model replicated the observed temporal patterns and elimination kinetics of [¹⁴C]PT equivalents in blood and urine during and following repeated dermal dosing and replicated the observed dose-dependencies of absorption, blood [¹⁴C]PT equivalents and plasma PT concentrations. The model provided internal dosimetry predictions for a benchmark dose analysis of hindlimb weakness in rats that combined dermal, gavage and dietary studies into a single internal dose–response model with area-under-the-curve (AUC) for plasma PT, the toxic moiety in the rat, as the internal dose metric. This PBPK model has predictive validity for calculating internal doses of PT and/or [¹⁴C]PT equivalents from different routes of exposure in the rat.

摘要

广谱抗菌/抗真菌吡啶硫酮锌 (ZnPT) 用于从防污漆到去头屑洗发水等产品。ZnPT 的危害特征是基于全面的毒理学测试确定的，并且含有这种杀菌剂的产品已安全使用多年。本研究的目的是为大鼠中的 ZnPT 建立基于皮肤生理学的药代动力学 (PBPK) 模型，以改进对 ZnPT 诱导毒性的剂量反应分析，其中可逆的后肢无力是用作 ZnPT 风险评估基础的终点。以前，我们开发了一种 PBPK 模型，该模型模拟了口服 ZnPT 给药后大鼠血液和组织中吡啶硫酮 (PT) 及其主要代谢物 2-（甲基磺酰基）吡啶和 S-葡萄糖醛酸结合物的动力学。皮肤模型优化使用使用大鼠皮肤进行的体外皮肤渗透研究和使用大鼠进行的皮肤重复剂量研究的历史数据。该模型在重复经皮给药期间和之后复制了观察到的血液和尿液中[ ¹⁴ C] PT 等效物的时间模式和消除动力学，并复制了观察到的吸收剂量依赖性，血液 [ ¹⁴C]PT当量和血浆PT浓度。该模型为大鼠后肢无力的基准剂量分析提供了内部剂量学预测，该模型将皮肤、灌胃和饮食研究结合到一个单一的内部剂量反应模型中，该模型具有血浆 PT（毒性部分）的曲线下面积 (AUC)在大鼠中，作为内部剂量指标。该 PBPK 模型对于计算来自大鼠不同暴露途径的PT 和/或 [ ¹⁴ C]PT 等效物的内部剂量具有预测有效性。